This grant application titled, Large Animal Model for Novel Autologous Treatments of Alveolar Clefts is a Mentored Clinical Scientist Research Career Development Award (K08) application under the guidance of Eric Everett (UNC, School of Dentistry) and Jorge Piedrahita (NCSU, College of Veterinary Medicine). The training and research plan represent outgrowths of the candidate's clinical work and emerging translational research; the research project centers on the most pressing current clinical dilemma faced in Pediatric Craniofacial Surgery: absence of bone. These defects result in profound distortions of facial features, major functional debilities, which, when expressed at the extreme, lead to an inability to eat, speak and breathe, creating immense hurdles to productive integration into society. Starting 4 years ago, the candidate's clinical practice began experiencing an increase in parents seen for prenatal consultations secondary to ultrasound diagnoses of craniofacial deformities--primarily clefts of the lip and palate. Because of these changing demographics and the candidate's interest in translational stem cell therapies, the possibility of using umbilical crd (UC) mesenchymal stem cells (MSCs) for novel therapeutics drew increased interest. Historically, much of the initial discussion with parents centered on the inter-disciplinary and long-term surgical care that would be required by their children. Now, the discussion includes the role that mesenchymal stem cells from their children's umbilical cord may play in future surgical care. The long-term goal of this mentored grant is to improve the algorithm of care for craniofacial deformities, through novel therapeutics generated from UC MSCs. The overall goals of this career development grant are to provide the candidate with the necessary didactic and experiential learning to facilitate his transition to an independent investigator and to develop a surgically created juvenile porcine alveolar cleft model to test novel treatments for the alveolar cleft. Aim I develops the model with the use of rib and cancellous bone grafts. After initiating th model, Aim 2 will test autologous porcine UC MSCs within the surgically created cleft; Aim 3 will compare porcine and human UC MSCs for translation of this knowledge to autologous use of cord MSCs in children. To accomplish the goals of this grant, the candidate has access to a unique collaborative environment that includes Craniofacial Geneticists, Veterinarians, Basic Scientists, and Bioengineers that draw from the resources of the UNC Schools of Medicine and Dentistry, and from the NCSU College of Veterinary Medicine. There are programmatic links between these schools and individuals that will allow on-going interactions with a very diverse group of clinicians and researchers who focus on the craniofacial region. The presence of this broad collaboration has challenged and broadened the candidate's thoughts about solutions to the problems faced by these craniofacial patients. The primary mentor, Eric T. Everett has an established record of NIH funding through NIDCR, and of mentoring scientists; the co-mentor, Jorge Piedrahita, similarly has an established record of NIH funding with a history of mentoring junior scientists. The Research Advisory Committee members, Susan Henning, Nancy Allbritton, Elizabeth Loboa, and Richard Fish, each bring distinct strengths to the Committee. Dr. Henning has a long-history of mentoring surgeon scientists. Dr. Allbritton is a physician scientist who provides an example for the candidate's future career growth and development, and has expertise in bioengineered mechanisms to control single cell function. Dr. Loboa has a broad capacity to perform biomechanical testing of engineered bone. Richard Fish has a long-standing history of work with large animal models. A consultant on the mentored grant, Dr. Sue Herring, has significant experience with porcine models to test craniofacial treatment strategies. The members of the Research Advisory Committee are accomplished researchers in their respective fields and will provide insights into the porcine animal model, manipulating mesenchymal stem cells, and measuring mechanical characteristics of tissue engineered bone on both a micro- and macro- level. The goals during this four-year award period are to become a more accomplished scientist, with deeper understanding of research design, the ethical treatment of human subjects and animals, and a broader vision of the role of stem cell therapeutics and nanotechniques for the purposes of translational biomedical tissue engineering. The four-year framework of the grant will provide the tools and skills to become an independent researcher, and also facilitate development as a mentor for the next generation of surgeon scientists. The candidate will use the training and research accomplished in this award to generate preliminary data for a competitive R01 grant application. PUBLIC HEALTH RELEVANCE: Congenital or acquired absence of craniofacial bone in humans results in profound distortions of facial features and major functional disabilities which can cause immense hurdles to productive integration into society. The immediate goal of this research is to develop a large animal alveolar cleft model to test novel cell-based treatment for early correction of craniofacial bone defects. The long-term goal is to be able to translate these findings to children using human cells.